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Molecular genetic analysis of 30 families with Joubert syndrome.
Clin Genet. 2016 12; 90(6):526-535.CG

Abstract

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Authors+Show Affiliations

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.Department of Genetics, Sultan Qaboos University Hospital, Muscat, Oman.Yokohama City University Medical Center, Children's Medical Center, Yokohama, Japan.Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan.Department of Pediatrics, Graduate school of Medicine, Yokohama City University, Yokohama, Japan.Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.Kumamoto City Child Development Support Center, Kumamoto, Japan.Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.Division of Child Neurology, Okinawa Prefectural Southern Medical Center & Children's Medical Center, Okinawa, Japan.Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan.Department of Child and Adolescent Psychiatry, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.Department of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.Department of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.Division of Rehabilitation, Nagano Children's Hospital, Nagano, Japan.Department of Pediatric Rehabilitation, Hokkaido Medical Center for Child Health and Rehabilitation, Hokkaido, Japan.Nire-no-kai Children's Clinic, Hokkaido, Japan.Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan.Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan.Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, Japan.Department of Neonatology, Gunma Children's Medical Center, Gunma, Japan.Division of Medical Genetics, Gunma Children's Medical Center, Gunma, Japan.Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.Division of Medical Genetics, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai, Japan.Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan. Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, UK.Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.Department of Nephrology, Chiba Children's Hospital, Chiba, Japan.Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27434533

Citation

Suzuki, T, et al. "Molecular Genetic Analysis of 30 Families With Joubert Syndrome." Clinical Genetics, vol. 90, no. 6, 2016, pp. 526-535.
Suzuki T, Miyake N, Tsurusaki Y, et al. Molecular genetic analysis of 30 families with Joubert syndrome. Clin Genet. 2016;90(6):526-535.
Suzuki, T., Miyake, N., Tsurusaki, Y., Okamoto, N., Alkindy, A., Inaba, A., Sato, M., Ito, S., Muramatsu, K., Kimura, S., Ieda, D., Saitoh, S., Hiyane, M., Suzumura, H., Yagyu, K., Shiraishi, H., Nakajima, M., Fueki, N., Habata, Y., ... Matsumoto, N. (2016). Molecular genetic analysis of 30 families with Joubert syndrome. Clinical Genetics, 90(6), 526-535. https://doi.org/10.1111/cge.12836
Suzuki T, et al. Molecular Genetic Analysis of 30 Families With Joubert Syndrome. Clin Genet. 2016;90(6):526-535. PubMed PMID: 27434533.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular genetic analysis of 30 families with Joubert syndrome. AU - Suzuki,T, AU - Miyake,N, AU - Tsurusaki,Y, AU - Okamoto,N, AU - Alkindy,A, AU - Inaba,A, AU - Sato,M, AU - Ito,S, AU - Muramatsu,K, AU - Kimura,S, AU - Ieda,D, AU - Saitoh,S, AU - Hiyane,M, AU - Suzumura,H, AU - Yagyu,K, AU - Shiraishi,H, AU - Nakajima,M, AU - Fueki,N, AU - Habata,Y, AU - Ueda,Y, AU - Komatsu,Y, AU - Yan,K, AU - Shimoda,K, AU - Shitara,Y, AU - Mizuno,S, AU - Ichinomiya,K, AU - Sameshima,K, AU - Tsuyusaki,Y, AU - Kurosawa,K, AU - Sakai,Y, AU - Haginoya,K, AU - Kobayashi,Y, AU - Yoshizawa,C, AU - Hisano,M, AU - Nakashima,M, AU - Saitsu,H, AU - Takeda,S, AU - Matsumoto,N, Y1 - 2016/09/26/ PY - 2016/05/13/received PY - 2016/06/27/revised PY - 2016/07/14/accepted PY - 2016/7/20/pubmed PY - 2017/7/8/medline PY - 2016/7/20/entrez KW - Japanese KW - Joubert syndrome KW - Whole-exome sequencing KW - concomitant mutations SP - 526 EP - 535 JF - Clinical genetics JO - Clin. Genet. VL - 90 IS - 6 N2 - Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes. SN - 1399-0004 UR - https://www.unboundmedicine.com/medline/citation/27434533/Molecular_genetic_analysis_of_30_families_with_Joubert_syndrome_ L2 - https://doi.org/10.1111/cge.12836 DB - PRIME DP - Unbound Medicine ER -